Summary assay for small molecule inhibitors of HIF-2a

Most solid tumors and their metastases experience regions of hypoxia, which promotes both tumor progression and resistance to therapy. Critical mediators of the hypoxic response are the hypoxia-inducible factors HIF-1alpha and HIF-2alpha. HIF-1alpha and HIF-2alpha are non-redundant and regulate both overlapping and unique downstream target genes. HIF-1alpha has been associated with poor patient more ..

Most solid tumors and their metastases experience regions of hypoxia, which promotes both tumor progression and resistance to therapy. Critical mediators of the hypoxic response are the hypoxia-inducible factors HIF-1alpha and HIF-2alpha. HIF-1alpha and HIF-2alpha are non-redundant and regulate both overlapping and unique downstream target genes. HIF-1alpha has been associated with poor patient survival in multiple tumor types and is currently being pursued as a target for inhibition for cancer therapy 1, 2. HIF-2alpha has also been associated with poor patient prognosis in specific tumor types such as renal cell carcinoma (RCC), neuroblastoma, glioblastoma (GBM) and non-small cell lung cancer (NSCLC) 3-6. The tumor type specific function of HIF-2alpha has been linked with the ability of HIF-2alpha (but not HIF-1alpha) to co-operate with a number of oncoproteins such as c-Myc, EGFR and K-Ras 5, 7, 8, and also to activate genes involved in proliferation, invasion and in the maintenance of cancer stem cells (CSCs) 9, 10. Hence, although the validity of HIF-1alpha as a target in multiple tumor types cannot be denied, emerging data suggest that in certain settings, the specific inhibition of HIF-2alpha versus HIF-1alpha would be warranted. Additionally, the newly established role of HIF-2alpha in the maintenance of neoplastic but not in normal stem cells, suggests that HIF-2alpha inhibition may provide a novel strategy for the targeting of CSCs 11, 12, 13. Thus our hypothesis is that the specific inhibition of HIF-2alpha will be a useful strategy for treating HIF-2alpha driven tumors and for targeting the CSC population. The overall goal of the study is to identify small molecule specific inhibitors of HIF-2alpha that will lead to the development of new anti-cancer therapies.